Abstract 869: Potent in vitro and in vivo anti-tumor activity of PI3K inhibitor BAY 80-6946 and MEK inhibitor BAY 86-9766 in preclinical biliary tract cancer models

Abstract Biliary tract cancer (BTC) includes a spectrum of genetically diverse invasive adenocarcinomas consisting intra- and extrahepatic cholangiocarcinoma (CC), and carcinoma arising from the gall bladder (GBC). Only 10% of patients diagnosed with early-stage disease are considered candidates for surgical resection, which offers the only chance for cure. The prognosis is poor for the majority of patients with locally advanced or metastatic BTC with a median survival of under a year. Recently, high incidence of oncogenic mutations such as KRAS, BRAF, PIK3CA and EGFR were found in BTC patients, potentially rendering these patients sensitive to inhibitors of these pathways. We report on preclinical evaluation of highly potent and selective PI3K inhibitor BAY 80-6946 and allosteric MEK inhibitor BAY 86-9766 in BTC as single agent and in combination. In vitro profiling a panel of BTC tumor cell lines indicated that KRASmut and PIK3CAmut cell lines were sensitive to MEKi (BAY 86-9766) and PI3Ki (BAY 80-6946), respectively, compared to the cell lines with wild type KRAS and PIK3CA. However, although MEKi BAY 86-9766 inhibited proliferation with IC50s of 147 nM in HuCCT-1 (KRASG12D) and 137 nM in EGI-1 (KRASG12D) cell lines, it can neither reach IC90 nor induce tumor apoptosis at concentration up to10 µM, indicating activation of additional survival pathways in these KRASmut BTC cell lines. When combining MEKi BAY 86-9766 with PI3Ki BAY 80-6946 in KRASmut EGI-1, IC90 could be reached at much lower concentrations, e.g. 108 nM of MEKi with 81 nM of PI3Ki in EGI-1 cells. Furthermore, strong activation (10-fold) of caspase3/7 was observed when EGI-1 cells were treated with 700 nM of MEKi with 230 nM of PI3Ki. To confirm the observed in vitro synergies, anti-tumor efficacy of BAY 80-6946 and BAY 86-9766 in mono- as well as combination therapy was evaluated in a set of human BTC xenograft models. Similar to the in vitro results, robust in vivo antitumor activities were observed in the PI3Ki and MEKi combination groups compared to monotherapy arms. Further detailed molecular mechanism on the synergistic inhibition of BTC tumor growth by combination of PI3K and MEK inhibitors, as well as in vitro and in vivo comparison to the chemotherapeutics will be presented. In conclusion, PI3Ki and MEKi combination therapy might open a new treatment paradigm for BTC to be developed in clinic. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 869. doi:1538-7445.AM2012-869